Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

酗酒问题 (PAU) 是全世界死亡和残疾的主要原因。尽管全基因组关联研究已经确定了 PAU 风险基因，但该性状的遗传结构尚未完全了解。我们对 435,563 名欧洲血统个体进行了 PAU 代理表型荟萃分析，将酒精使用障碍和酗酒问题结合起来。我们确定了 29 个独立的风险变异，其中 19 个是新颖的。 PAU 与 138 种表型具有遗传相关性，包括物质使用和精神特征。独立生物库样本（BioVU， n = 67,589）中的全表型多基因风险评分分析证实了 PAU 与物质使用和精神疾病之间的遗传相关性。 PAU 的遗传力在大脑以及保守和调控基因组区域中丰富。孟德尔随机化表明物质使用、精神状况、冒险行为和认知表现对 PAU 的责任有因果影响。总之，这项大型 PAU 荟萃分析确定了新的风险位点，并揭示了与许多其他性状的遗传关系。